title: MET and ERBB2 are coexpressed in ERBB2+ breast cancer and contribute to innate resistance.
abstract: Breast cancer displays significant intratumoral heterogeneity, which has been shown to have a substantial impact on both innate and acquired resistance to tyrosine kinase inhibitors. The heterogeneous expression of multiple receptor tyrosine kinases (RTK) in cancers supports tumor signaling robustness and plays a significant role in resistance to targeted inhibition. Recent studies have revealed interactions between the MET receptor and the ERBB receptor family in the therapeutic resistance of several cancers. In this study, the relationship between MET expression/activity and the expression/activity of the ERBB receptor family in human breast cancer was interrogated. Importantly, a significant percentage of ERBB2(+) tumors coexpressing MET and ERBB2 were observed and displayed significant heterogeneity with subpopulations of cells that are MET(-)/ERBB2(+), MET(+)/ERBB2(-), and MET(+)/ERBB2(+). In a MET(+)/ERBB2(+) breast cancer cell line, MET depletion resulted in increased ERBB2 activation, and conversely, ERBB2 depletion resulted in increased MET activation. Neither EGFR nor ERBB3 compensated for MET or ERBB2 knockdown. The loss of either MET or ERBB2 led to a decrease in PI3K/AKT signaling and increased dependency on MAPK. These data show that a subset of ERBB2(+) breast cancers express MET and contain MET(+)/ERBB2(+) subpopulations. Moreover, analysis of RTK activation during ERBB2 knockdown indicated that MET signaling is a compensatory pathway of resistance.
  
  
  CONCLUSIONS
  ERBB2(+) breast cancers with MET(+)/ERBB2(+) subpopulations may have an innate resistance to ERBB2 inhibition and may benefit from combined MET and ERBB2 inhibition.
authors.affiliation: Van Andel Research Institute, 333 Bostwick Avenue NE, Grand Rapids, MI 49503. Carrie.Graveel@vai.org.
authors.forename: Amanda K
authors.initials: AK
authors.lastname: Paulson
authors.forename: Erik S
authors.initials: ES
authors.lastname: Linklater
authors.forename: Bree D
authors.initials: BD
authors.lastname: Berghuis
authors.forename: Colleen A
authors.initials: CA
authors.lastname: App
authors.forename: Leon D
authors.initials: LD
authors.lastname: Oostendorp
authors.forename: Jayne E
authors.initials: JE
authors.lastname: Paulson
authors.forename: Jane E
authors.initials: JE
authors.lastname: Pettinga
authors.forename: Marianne K
authors.initials: MK
authors.lastname: Melnik
authors.forename: George F
authors.initials: GF
authors.lastname: Vande Woude
authors.forename: Carrie R
authors.initials: CR
authors.lastname: Graveel
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D020935:MAP Kinase Signaling System; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism
chemical_list: D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C491743:MET protein, human